Introduction

The management of asthma in young children is associated with many challenges. The diagnosis could be difficult as wheezing can occur in this age without asthma and confirmatory lung function tests are difficult to perform.1 Also, many medications for asthma are poorly studied in very young children. The diagnosis of asthma in young children is based largely on symptom patterns (wheeze, cough, breathlessness, activity limitation, and nocturnal symptoms) and frequency, combined with a clinical assessment of family history and physical findings. Around half of preschool wheezers become asymptomatic by school age irrespective of treatment.1,2

Asthma guidelines have been developed to increase the awareness of asthma among health professionals, to improve asthma management, to evaluate published reports on asthma and to promote international collaboration in asthma research.3 Paper-based implementations are by still the most popular approach but information technology in guideline implementation will probably rise based on the rising interest in electronic health records. Asthma guidelines improve patient care and practitioner performance regardless of the implementation method.4

The first international guidelines were formulated by the USA National Heart Lung and Blood Institute (NHLBI) in 1991.5 and this expert panel report was updated and reviewed several times and finally published in 2008 as an Expert Panel Report 3 (EPR-3).6 However, the first evidence based guidelines for asthma were published under GINA in 1995 and were revised in 2006. In 2009, GINA published a new guideline specifically addressing the management of asthma in children 5 years and younger.3,7 This was updated in 2015 in a pocket guide for health care professionals.1

Asthma Phenotypes in Young Children

As more is learned about the various phenotypes of asthma, the complexity of management will continue to grow.8 All guidelines point to the difficulties in making a firm diagnosis of asthma in children under 5 and several wheezy phenotypes have been identified.3 Preschool children consume a disproportionately high amount of health-care resources compared with older children and adults with wheeze or asthma. Findings from several cohort studies have shown that preschool children with wheeze have deficits in lung function at 6 years of age that persist until early and middle adulthood.9 Characteristics of the asthma-predictive phenotype in early childhood include male sex, history of wheezing with lower respiratory tract infections, history of parental asthma, history of atopic dermatitis, eosinophilia, early sensitization to food or aeroallergens, and lower lung function in early life.2

A study on long-term responses to inhaled anti-inflammatory medications based on childhood asthma phenotypes identified 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. The authors concluded that refined phenotypic classification might better inform treatment decisions. Cluster assignment identified two subsets of children providing clinicians with viable treatment options for patients at risk for corticosteroid-related complications. One cluster demonstrated a positive response to both budesonide and nedocromil compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide and nedocromil compared with placebo.10

Wheezing phenotypes were identified by means of latent class analysis in cohort of 3,739 children followed from birth in 29 primary care health centers in Spain. There were two early phenotypes which started wheezing at a median age of six months, one of which was transient while the other had a heavy recurrence of episodes. A third phenotype exhibited a delayed onset of wheezing, a constant rise in incidence through the first 36 months, and a relationship with allergic asthma.11

Phenotyping asthma by multivariate analyses and more recently by unsupervised analysis of children cohorts revealed three wheeze phenotypes in preschool age: the mild episodic viral wheeze phenotype; the multi-trigger atopic wheeze; and the less often encountered severe non-atopic wheeze. Early onset of allergy in asthma (more prevalent in boys) was associated with poor prognosis unlike the severe non-atopic wheeze phenotype which had a female predominance. The prognosis of the severe non-atopic wheeze depends on time of onset (early or late) of allergic expression.12 A prospectively followed cohort was phenotyped using cluster analysis and wheezing trajectories were assessed by crossing the original phenotypes with the phenotypes obtained at 5 years. Remission was most frequently observed in mild early viral wheeze while persistence was observed in atopic multiple-trigger wheeze and those with non-atopic uncontrolled wheeze developed severe uncontrolled wheeze in most cases.13

Novel immune phenotypes for childhood Allergic and non-allergic asthma were identified from a cohort of 4-15 year olds. The authors observed increased Treg cells in patients with allergic asthma compared with healthy controls but not those in non-allergic asthma. A decreased innate immunity genes was noted in patients with allergic asthma, the first potentially indicating a counter-regulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Patients with non-allergic asthma showed IL-17-shifted proinflammatory immunity, promoting neutrophil inflammation, and less functional Treg cells.14

The 2015 GINA Guidelines for Children 5 Years and Under1

The goals of asthma management in young children are to achieve good control of symptoms and maintain normal activities, minimize risk of flare-ups, maintain lung functions, and minimize side effects from medications. The Global Initiative for Asthma (GINA) offered a stepwise approach to treatment that is customized to the individual child taking into account the effectiveness of available medications, their safety, and their cost to the payer or family.

According to the 2015 GINA guidelines, asthma treatment steps proposed for children 5 years and younger are as follows:

Step 1: As-needed inhaled short-acting beta2-agonist (SABA)

Step 2: Initial controller treatment, plus as-needed SABA. Regular daily low dose inhaled corticosteroid (ICS) is recommended as the preferred initial controller treatment. It should be given for at least 3 months to establish its effectiveness in achieving good asthma control. As an alternative, leukotriene receptor antagonist (LTRA) may be considered.

Step 3: Additional controller treatment plus as-needed SABA. For children whose symptoms are not controlled after 3 months of low dose ICS, doubling the initial dose is often the best option. Another option is adding LTRA to low-dose ICS. This step up should be preceded by considering other diagnoses and checking on inhaler techniques and adherence.

Step 4: Continue controller treatment and refer for expert assessment for further diagnosis and investigation. Addition of regular LTRA or increasing the dose or frequency of ICS is another option to be considered.

Treatment adjustment is based on regular reviewing of the child’s response (every 3-6 months). Asthma-like symptoms remit in a substantial proportion of children aged 5 years and younger, so stepping down treatment should be considered. In addition, marked seasonal variations may be seen in symptoms. For some children with only seasonal symptoms, daily long term controller therapy can be discontinued. In that case, a follow-up visit 3-6 weeks later to check whether symptoms have recurred, as therapy may need to be reinstituted.

A flare-up or exacerbation is defined as an acute or sub-acute deterioration in symptom control that is sufficient to cause distress and necessitates a visit to a health care provider or requires treatment with systemic corticosteroids. An asthma action plan should enable family members and care givers to recognize asthma worsening or flare-up, initiate treatment, and identify when urgent hospital care is necessary. Initial pharmacotherapy for mild-moderate exacerbations include higher or more frequent doses of SABA, ipratropium bromide for children who fail to respond to SABA, and a 3-5 days’ treatment with oral corticosteroids (prednisolone or equivalent) may be considered.

Urgent transfer to hospital is indicated in case of any of the following 3 situations. First, if there is actual or impending respiratory arrest, inability to speak or drink, central cyanosis, subcostal retractions, oxygen saturation < 92% in room air, or silent chest on auscultation. Second, if there is lack of response to initial bronchodilator therapy namely 6 puffs of inhaled SABA over 1-2 hours or persistent tachypnea despite 3 administrations of inhaled SABA. The third indication is when the social environment impedes delivery of acute treatment at home.

Other available guidelines for asthma management in young children

The PRACTALL guidelines for asthma were published in 2008 by an expert team nominated by the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy Asthma and Immunology (AAAAI). In these guidelines, at least four patterns of wheezing were proposed. These include "transient wheezing" in the first 2 years of life only, "non-atopic wheezing" triggered by viral infections and remitting in later childhood, "persistent asthma" with atopy, eosinophilia, food allergy, a positive parental history and high indoor exposure to allergens, and "severe intermittent wheezing" with infrequent episodes and minimal morbidity between episodes but with atopic characteristics.15

These guidelines recommended a step up protocol for preventive pharmacological treatment in children older than 2 years of age. The treatment algorithm commences with an option of inhaled corticosteroids (ICS), beclomethasone dipropionate (BDP), 200 μg equivalent or montelukast, 4 mg for 2 years and 5 mg for 5 years and upwards. If control is insufficient, the ICS can be increased to BDP 400 μg equivalent or add an ICS to montelukast. Should this step not lead to control of symptoms, the ICS can be increased to BDP 800 μg equivalent or montelukast can be added to the higher dose ICS. A long acting beta2 agonist also can be added to the ICS before considering other options such as theophylline, oral corticosteroids or omalizumlab.3,15

The European Respiratory Society (ERS) Task Forceproduced a guideline document in 2008, using an evidence based approach (Grading of Recommendations Assessment, Development and Evaluation GRADE) in an attempt to improve the management in children 5 years or less with wheezy illnesses. The authors proposed that wheeze in young children should be classified as "episodic" (viral) or "multiple trigger" wheeze, which are not mutually exclusive.3,16,17

The 2008 ERS guidelines recommended that for "multiple trigger wheeze", treatment should be initiated with a trial of an ICS, up to BDP 400 μg equivalent, or fluticasone, 200 μg per day for a period of about 3 months. Marked variation in response occurs; patients with frequent symptoms aged 2 years or older and with a family history of asthma respond best to treatment with ICS. Children aged 2 years or younger without a family history of asthma and less frequent symptoms have no significant treatment effect.17,18 The ERS guidelines note that the use of ICS in preschool children with episodic viral wheeze does not reduce the risk of persistent wheeze at the age of 6 years and that symptoms return when glucocorticoid therapy is discontinued. Daily use of montelukast over a one year period in young children reduced wheezy episodes by 32% and resulted in a 30% reduction in unscheduled health visits but had no effect on hospitalizations compared with placebo.3,17

The NHLBI Expert Panel Report: The 2007 Expert Panel Report5 of the US National Heart, Lung and Blood institution (NHLBI) Guidelines were published before the PRACTALL, ERS and GINA 2009 guidelines. It contained a special section on management of children, 0-4 years.

These guidelines stress that 50-80% of children who have asthma develop symptoms before their fifth birthday, but the disease is not often diagnosed as such. Children under 3 years of age who have more than four episodes of wheezing in the past year which affects sleep are more likely to develop persistent asthma after the age of 5, particularly if there is a parental history of asthma, evidence of food sensitization, a greater than 4% peripheral blood eosinophilia or wheezing apart from colds.19

The report mentioned the use of daily low dose ICS to reduce the risk in infants who need systemic corticosteroid therapy within 6 months (Evidence D), age appropriate dietary intake of calcium and vitamin D for children who are required to receive high dose ICS or systemic corticosteroids (Evidence D), and alternative treatment including montelukast (Evidence A). Theophylline is not recommended for children 5 years and younger. These guidelines also permit the use of a long acting Beta agonist (LABA) as add on treatment although there are no enough studies on the efficacy or safety of LABA as add on treatment in young children. These guidelines also provide useful checklists for parents when children are discharged `from the hospital and information on the practical use of spacers and inhalers.3

EPR-3 treatment recommendations at step 3 and above in children 0–4 years are based upon data extrapolated from older children and adults, and also on expert opinion. Studies are needed to address the large gaps in this population. Specifically, combination therapy with ICS + LABA has not been studied in children under 4 years of age. Furthermore, no comparator trials of add-on therapies have been completed.20

BTS/SIGN British Guideline on the Management of Asthma 2014 provided recommendations based on current evidence for best practice in the management of asthma in all ages including children under 5 years. The document stated that Inhaled corticosteroids (ICS) are the recommended preventer drug for achieving overall treatment goals (evidence A) and that the first choice as add-on therapy to ICS in children under five years old is a leukotriene receptor antagonist (evidence B). The guideline recommended considering steroid tablets early in the management of severe asthma in infants (evidence B). It also concluded that exposure to cats and/or dogs in infancy does not impact on a diagnosis of asthma, although may influence allergic sensitization, and that parents should not make choices on pet ownership based on the desire to prevent or reduce asthma symptoms (evidence B). Breast feeding should be encouraged for its many benefits, including a potential protective effect in relation to early asthma (evidence C). Parents and parents-to-be should be advised of the many adverse effects of smoking including increased wheezing in infancy and increased risk of persistent asthma (evidence B). All childhood immunizations should proceed normally as there is no evidence of an adverse effect on the incidence of asthma (evidence C). Lung function measurements cannot be reliably used to guide asthma management in children under five years of age.21

The Japanese guideline for the diagnosis and treatment of allergic diseases JAGL2013provided information on diagnosis by age group from infancy to puberty (0-15 years of age). JAGL differs from the GINA 2009 Guideline in that it emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. JAGL has also introduced treatment and management. Using a control test on children, JAGL recommended avoiding exacerbating factors and appropriate use of anti-inflammatory drugs.22

Unmet Needs

Despite significant advances in the treatment of asthma and the development of evidence-based and evidence-informed guidelines, childhood asthma morbidity remains high.24 While written action plans are standard in the treatment and management of asthma, significant variability exists in the content and format among plans. This variability results in inconsistent educational messages that lend themselves to patient confusion and suboptimal health outcomes.25 Another weak point is education. Asthma education should not be regarded as a single event but rather as a continuous process, repeated and supplemented at every subsequent consultation. Importantly, education should highlight the importance of adherence to prescribed medication even in the absence of symptoms, and should involve literal explanation and physical demonstration of the optimal use of inhaler devices and peak flow meters. Education should be tailored according to the socio-cultural background of the family. Improving uptake of asthma management plans, both by families and by practitioners, is needed.23,26

References

Global Initiative for Asthma (GINA). Pocket Guide for Asthma Management and Prevention in Children 5 Years and Younger, updated April 2015. Available from: http://www.ginasthma.org/local/uploads/files/GINA_PediatricPocket_2015.pdf.

BTS/SIGN British Guideline on the Management of Asthma, October 2014. Available from: https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2014/. Cited on May 15, 2015.